Rotavirus disease causes nearly 1 million infant deaths annually worldwide. The only approved rotavirus vaccine, a live vaccine, was withdrawn from the market in 1999 because of association with intussusception. The safety concerns associated with live vaccines currently in development can be remedied by the development of an efficacious and safe subunit mucosal vaccine. The rotavirus VP6 protein delivered intranasally with enterotoxin adjuvants induces a long lasting immune response that protects mice from oral challenge with a virulent mouse rotavirus. However, attenuated enterotoxin adjuvants in human vaccines pose valid safety concerns that lead to the evaluation of other adjuvants. Parallel Solutions Inc. has developed a powerful polyphosphazene immunoadjuvant platform capable of controlled modulation and optimization. It has been demonstrated that VP6 vaccine adjuvanted with the lead polyphosphazene compound, PCPP, induced 80% immune protection when delivered intranasally in mice. Preliminary results indicate that chemical derivatives of PCPP can enhance immunoadjuvant activity up to 500 times. Polyphosphazenes can also be formulated as microspheres and their structural characteristics can be optimized for mucosal uptake. Consequently, a modulated and optimized polyphosphazene-VP6 formulation offers the potential to develop a safe, clinically and economically effective vaccine to a patient population with high unmet medical need. This proposal outlines experiments that will optimize the formulation of VP6 within polyphosphazene adjuvants. In Phase II SBIR studies, we will further optimize vaccine formulation, administration and production processes in safety and immunogencity trials. In Phase III SBIR studies, we will conduct safety, immunogencity and efficacy trials in humans and seek FDA approval.